Formulation of antiretroviral nanocrystals and development into a microneedle delivery system for potential treatment of HIV-associated neurocognitive disorder (HAND)

HIV/AIDS remains a major global public health issue. While antiretroviral therapy is effective at reducing the viral load in the blood, up to 50% of those with HIV suffer from some degree of HIV-associated neurocognitive disorder, due to the presence of the blood-brain barrier restricting drugs from crossing into the central nervous system and treating the viral reservoir there. One way to circumvent this is the nose-to-brain pathway. This pathway can also be accessed via a facial intradermal injection. Certain parameters can increase delivery via this route, including using nanoparticles with a positive zeta potential and an effective diameter of 200 nm or less.

Highlights

• Nanocrystals of rilpivirine and cabotegravir were formulated.
• These nanocrystals were loaded into hollow microneedle systems were for use in vivo.
• An in vivo study shows the potential of these systems to be used to deliver antiretrovirals to the brain for treatment of HAND.

Microneedle arrays offer a minimally invasive, pain-free alternative to traditional hypodermic injections. This study shows the formulation of nanocrystals of both rilpivirine (RPV) and cabotegravir, followed by incorporation into separate microneedle delivery systems for application to either side of the face. Following an in vivo study in rats, delivery to the brain was seen for both drugs. For RPV, a C_max was seen at 21 days of 619.17 ± 73.32 ng/g, above that of recognised plasma IC90 levels, and potentially therapeutically relevant levels were maintained for 28 days. For CAB, a C_max was seen at 28 days of 478.31 ± 320.86 ng/g, and while below recognised 4IC90 levels, does indicate that therapeutically relevant levels could be achieved by manipulating final microaaray patch size in humans.

2.1. Materials

PVA 9-10 kDa, D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS), trifluoroacetic acid (TFA) (suitable for HPLC, ≥ 99.0%), acetonitrile (ACN) (suitable for HPLC, gradient grade, ≥ 99.9%), trehalose, mannitol, chitosan (medium molecular weight), methyl cellulose, phosphate buffered saline (PBS) pH 7.2-7.6 and acetic acid (glacial, ReagentPlus®, ≥ 99.0%) were purchased from Sigma-Aldrich (St. Louis, MO, USA). PVP 58 kDa and PVP 360 kDa, marketed as Plasdone™ k29/32 and Plasdone™ k90 respectively, were obtained from Ashland (Wilmington, DE, USA). RPV was provided by Janssen Pharmceutica (Beerse, Belgium). CAB was provided by ViiV Healthcare Ltd. (Brentford, UK). Poly(lactic acid) (PLA) was purchased from Ultimaker (Utrecht, Netherlands). Nanosoft™ hollow microneedle arrays were purchased from Fillmed (Paris, France). For the neonatal porcine skin that was used ex vivo, stillborn piglets were obtained from a local farm immediately after birth and excised full-thickness skin was stored at -20°C until further use.

Download the full study as PDF here: Formulation of antiretroviral nanocrystals and development into a microneedle delivery system for potential treatment of HIV-associated neurocognitive disorder (HAND)

or read it here

Marco T.A. Abbate, Inken K. Ramöller, Akmal H. Sabri, Alejandro J. Paredes, Aaron J. Hutton, Peter E. McKenna, Ke Peng, Jessica A. Hollett, Helen O. McCarthy, Ryan F. Donnelly, Formulation of antiretroviral nanocrystals and development into a microneedle delivery system for potential treatment of HIV-associated neurocognitive disorder (HAND), International Journal of Pharmaceutics, 2023, 123005, ISSN 0378-5173,
https://doi.org/10.1016/j.ijpharm.2023.123005.

Read more about Chitosan: